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Author Notes:

Correspondence: Bum-Yong Kang, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Atlanta Veterans Affairs Healthcare, 1670 Clairmont Rd, Decatur, GA 30033; e-mail: bum-yong.kang@emory.edu

Author contributions: Contribution: B.-Y.K. created the concept, hypothesis delineation, and design; A.J.J., S.S.C., C.P., C.-M.L., R.L.B., M.J.P., J.M., D.R.A., R.L.S., C.M.H., and B.-Y.K. acquired, analyzed, and interpreted the data; and A.J.J., S.S.C., C.M.H., and B.-Y.K. wrote the article.

Acknowledgements: The authors thank Victor Tseng for his careful review and valuable editorial comments in preparation of the manuscript.

Disclosures: The authors declare no competing financial interests.


Research Funding:

This study was supported by funding from the National Institutes of Health, National Heart, Lung, and Blood Institute (grants R01 HL102167 [C.M.H. and R.L.S.], R01 HL119291 [C.P.], and R01 HL133053 [B.-Y.K.]),

Center for Drug Discovery (grant CDD-0075064) (R.L.S. and B.-Y.K.)

Veterans Affairs Biomedical Laboratory Research and Development (VA BLR&D) Merit Review Award (I01 BX004263) (C.M.H.)

Emory/Childrens Healthcare CEB (grant F16788-00) (B.-Y.K.).


  • Science & Technology
  • Life Sciences & Biomedicine
  • Hematology
  • Activated receptor gamma
  • Arterial hypertension
  • Chemical difference
  • Plasma endotholin-1
  • Chronic hypoxia
  • Expression
  • Anemia
  • Mice
  • Catheterization
  • Dysfunction

PPAR gamma increases HUWE1 to attenuate NF-kappa B/p65 and sickle cell disease with pulmonary hypertension

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Journal Title:

Blood Advances


Volume 5, Number 2


, Pages 399-413

Type of Work:

Article | Final Publisher PDF


Sickle cell disease (SCD)-associated pulmonary hypertension (PH) causes significant morbidity and mortality. Here, we defined the role of endothelial specific peroxisome proliferator-activated receptor g (PPARg) function and novel PPARg/HUWE1/miR-98 signaling pathways in the pathogenesis of SCD-PH. PH and right ventricular hypertrophy (RVH) were increased in chimeric Townes humanized sickle cell (SS) mice with endothelialtargeted PPARg knockout (SSePPARgKO) compared with chimeric littermate control (SSLitCon). Lung levels of PPARg, HUWE1, and miR-98 were reduced in SSePPARgKO mice compared with SSLitCon mice, whereas SSePPARgKO lungs were characterized by increased levels of p65, ET-1, and VCAM1. Collectively, these findings indicate that loss of endothelial PPARg is sufficient to increase ET-1 and VCAM1 that contribute to endothelial dysfunction and SCD-PH pathogenesis. Levels of HUWE1 and miR-98 were decreased, and p65 levels were increased in the lungs of SS mice in vivo and in hemin-treated human pulmonary artery endothelial cells (HPAECs) in vitro. Although silencing of p65 does not regulate HUWE1 levels, the loss of HUWE1 increased p65 levels in HPAECs. Overexpression of PPARg attenuated hemininduced reductions of HUWE1 and miR-98 and increases in p65 and endothelial dysfunction. Similarly, PPARg activation attenuated baseline PH and RVH and increased HUWE1 and miR-98 in SS lungs. In vitro, hemin treatment reduced PPARg, HUWE1, and miR-98 levels and increased p65 expression, HPAEC monocyte adhesion, and proliferation. These derangements were attenuated by pharmacological PPARg activation. Targeting these signaling pathways can favorably modulate a spectrum of pathobiological responses in SCD-PH pathogenesis, highlighting novel therapeutic targets in SCD pulmonary vascular dysfunction and PH.

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© 2021 by American Society of Hematology.

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